Two different subhuman primate models have been used to study HIV-1 pathogenesis and the development of a prophylactic vaccine. Chimpanzees: Following resolution of a primary HIV-1 infection initially induced by inoculating a mixture of three different virus strains, a chimpanzee was exposed to both immunostimulatory and immunosuppressive agents in an attempt to assess the contributions of different components of the immune system in suppressing circulating virus. The infusion of human leukocytes as an allogeneic stimulus induced the replication of one of the input virus strains that had not previously been isolated or detected by PCR. The administration of high-dose, 17 day courses of corticosteroids resulted in coordinate and transient increases of each of the three viruses present in the original inoculum and elevation of HIV-1 specific ELISA antibody levels. Steroids administered to a second chimpanzee, chronically infected with a single HIV-1 isolate, also induced elevations of cell-associated virus. To test whether the protective effects of attenuated SIV vaccines in macaques were applicable to the HIV-1/chimpanzee system, 2 groups of animals, previously infected with HIV-1(IIIB) or HIV-1(SF2), were each challenged with a heterologous clade B virus, HIV-1(DH12). In contrast to an HIV-1 naive chimpanzee that rapidly became infected following the inoculation of HIV-1(DH12), the two HIV-1(IIIB) previously infected chimpanzees resisted repeated and escalating inoculations of HIV-1(DH12), as monitored by virus isolation and PCR. The two previously HIV-1(SF2) infected animals became infected with HIV-1(DH12), but in contrast to the HIV-1 naive chimpanzee, no cell-free viral RNA was detected in the plasma by RT PCR and levels of PBMC-associated viral DNA were reduced 35 to 50-fold. Macaques: A series of SIV-HIV-1 chimeric viruses (SHIVs) were constructed and evaluated for their capacity to induce disease following inoculation into macaque monkeys. SHIVs containing the HIV-1 vpr, tat, rev, vpu, and env genes consistently induced rapid CD4 loss (within 2 to 3 weeks) following administration of virus prepared in PBMC from the inoculated animal (autologous virus); the SIV nef gene was required for reproducible disease induction. This system is being used to investigate critical events occurring during the first weeks of in vivo infection because of the very rapid and irreversible loss of CD4 cells observed.